Processes for the preparation of heterocyclic hydroxyamines and intermediates and catalysts for use therein

ABSTRACT

A process for the preparation of a compound of Formula (1): 
                         
wherein: X is S, O or NR 3 , wherein R 3  is H or an organic group; R is H or an organic group; R 1  and R 2  each independently are H, optionally substituted alkyl or optionally substituted aryl; G is a substituent; and n is 0 to 3:
 
which comprises the steps:
     (a) reacting a compound of Formula (2) with a compound of Formula NHR 1 R 2  to give a compound of Formula (3):   
                         
wherein X, R, G and n are as defined above and R 4  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or a combination thereof; and
     (b) reducing the compound of Formula (3) to give a compound of Formula (1) is provided.   
     Processes for the preparation of a compounds of Formula (2), novel compounds of Formula (3) and certain preferred catalysts of formula: 
                         
wherein: R 6  represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand; A represents an optionally substituted nitrogen; B represents an optionally substituted nitrogen, oxygen, sulphur or phosphorous; E represents a linking group; M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site; provided that at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom, are also provided.

This invention relates to processes for the preparation of heterocyclichydroxyamines and to novel substituted heterocycles and catalysts.

Heterocyclic hydroxyamines are important intermediates in the synthesisof many pharmaceuticals. For example Duloxetine((+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine), a 5-HT andnorepinephrine uptake inhibitor, is showing considerable promise as apotential treatment for depression and urinary incontinenance (U.S. Pat.Nos. 5,023,269, 4,956,388 and for a review see Current Opinion inInvestigational Drugs (PharmaPress Ltd.) (2000), 1(1), 116-121).

Processes for the manufacture of Duloxetine have been described inDeeter, et al., Tetrahedron Letters, 31(49), 7101-04 (1990); EP654264;U.S. Pat. No. 5,023,269; Liu et al., Chirality, 12(1), 26-29 (2000);EP457559; and Wheeler et al., J. Labelled Compd. Radiopharm, 36(3),213-223 (1995).

According to the present invention there is provided a process for thepreparation of a compound of Formula (1):

wherein:

-   -   X is S, O or NR³, wherein R³ is H or an organic group;    -   R is H or an organic group;    -   R¹ and R² each independently are H, optionally substituted alkyl        or optionally substituted aryl;    -   G is a substituent; and    -   n is 0 to 3:        which comprises the steps:

-   (a) reacting a compound of Formula (2) with a compound of Formula    NHR₁R² to give a compound of Formula (3):

wherein X, R, G and n are as defined above and R⁴ is optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl or a combination thereof; and

-   (b) reducing the compound of Formula (3) to give a compound of    Formula (1).

A second aspect of the invention provides a process for the preparationof a compound of Formula (3) whereby a compound of Formula (2) isreacted with a compound of Formula NHR¹R² to give a compound of Formula(3).

A third aspect of the invention provides a process for the preparationof a compound of Formula (1) in which a compound of Formula (3) isreduced to give a compound of Formula (1).

When X is NR³, then R³ is preferably H, optionally substituted alkyl oroptionally substituted aryl, more preferably H or optionally substitutedC₁₋₄alkyl. It is especially preferred that when X is NR³ then R³ is H.

Preferably X is S.

Preferably n is 0.

Preferably R is H, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl,optionally substituted heterocyclyl or a combination thereof or ahydroxy protecting group such as benzyl, benzoyl or tetrahydropyranyl.

When R is optionally substituted alkyl, optionally substituted alkene oroptionally substituted alkyne it may be a linear, branched or cyclicmolecule.

It is particularly preferred that R is H; optionally substituted alkyl,especially optionally substituted C₁₋₄alkyl; or optionally substitutedaryl, especially optionally substituted phenyl or optionally substitutednapthyl.

It is especially preferred that R is H or napthyl.

Optional substituents for R are preferably selected from: alkyl(preferably C₁₋₄-alkyl), optionally substituted alkoxy (preferablyC₁₋₄-alkoxy), optionally substituted aryl (preferably phenyl),optionally substituted aryloxy (preferably phenoxy), polyalkylene oxide(preferably polyethylene oxide or polypropylene oxide), carboxy,phosphato, sulpho, nitro, cyano, halo, ureido, —SO₂F, hydroxy, ester,—NR^(a)R^(b), —COR^(a), —CONR^(a)R^(b), —NHCOR^(a), carboxyester,sulphone, and —SO₂NR^(a)R^(b) wherein R^(a) and R^(b) are eachindependently H or optionally substituted alkyl (especially C₁₋₄-alkyl)or, in the case of —NR^(a)R^(b), CONR^(a)R^(b) and —SO₂NR^(a)R^(b),R^(a) and R^(b) together with the nitrogen atom to which they areattached represent an aliphatic or aromatic ring system; or acombination thereof.

The substituent G is preferably selected from the optional substituentsas for R.

Preferably R¹ and R² are H or optionally substituted C₁₋₄alkyl. In apreferred embodiment one of R¹ and R² is H and the other is optionallysubstituted C₁₋₄alkyl. In an especially preferred embodiment one of R¹and R² is H and the other is methyl.

Optional substituents for R¹ and R² are preferably selected from:optionally substituted alkoxy (preferably C₁₋₄-alkoxy), optionallysubstituted aryl (preferably phenyl), optionally substituted aryloxy(preferably phenoxy), polyalkylene oxide (preferably polyethylene oxideor polypropylene oxide), carboxy, phosphato, sulpho, nitro, cyano, halo,ureido, —SO₂F, hydroxy, ester, —NR^(a)R^(b), —COR^(a), —CONR^(a)R^(b),—NHCOR^(a), carboxyester, sulphone, and —SO₂NR^(a)R^(b) wherein R^(a)and R^(b) are each independently H or optionally substituted alkyl(especially C₁₋₄-alkyl) or, in the case of —NR^(a)R^(b), CONR^(a)R^(b)and —SO₂NR^(a)R^(b), R^(a) and R^(b) together with the nitrogen atom towhich they are attached represent an aliphatic or aromatic ring system;or a combination thereof.

Preferably compounds of Formula (1) prepared by a process according tothe invention are of Formula (4):

wherein X, G, n, R, R¹ and R² are as defined above.

In a compound of Formula (2) R⁴ preferably is optionally substitutedalkyl or optionally substituted aryl, more preferably optionallysubstituted C₁₋₁₂ alkyl or optionally substituted benzyl. It isespecially preferred that R⁴ is optionally substituted C₁₋₄ alkyl,particularly ethyl.

Preferred optional substituents for R⁴ are as for R¹ and R².

Compounds of Formula (2) are preferably formed by acylating a compoundof Formula (5):

where X, G and n are as defined above, to give a compound of:

where X, G, n, and R⁴ are as defined above, followed by reduction of theBeta-keto group so formed and optionally alkylating the hydroxyl groupso formed.

The compound of Formula (5) is preferably acylated by a dialkylcarbonate.

Reduction of the Beta-keto group in compounds of Formula (6) may becarried out by any means known in the art to be able to reduce Beta-ketogroups in compounds such as those of Formula (6).

Preferably the reduction of the Beta-keto group in compounds of Formula(6) is achieved by reaction with a hydrogen source other than hydrogengas. The hydrogen source is preferably formic acid; iso-propanol;cyclohexadiene; an organic formate salt, especially triethylamine orammonia; an inorganic formate salt, especially potassium, sodium orlithium. More preferrably reduction of the Beta-keto group in compoundsof Formula (6) to give a compound of Formula (2) may be by reaction witha mixture a of formic acid and triethylamine, preferably in a molarratio of formic acid to triethylamine of from 10:1 to 1:1 and especiallyin a molar ratio of 5:2.

The reduction of the Beta-keto group in compounds of Formula (6) ispreferably a stereospecific reduction. The product of this reduction maybe either the (S) or the (R) isomer. Preferably the product is producedin at least 80% e.e., more preferably in at least 90% e.e., andespecially in at least 95% e.e. Preferably the product of the reductionis a compound of Formula (7):

Where X, G, n and R⁴ are as defined above.

When reduction of the Beta-keto group in a compound of Formula (6) is astereospecific reduction it may be carried out by any means known in theart for the stereospecific reduction of Beta-keto groups. These includethe use of chemical catalysts (for examples see Genet, J. P.;Ratovelomanana-Vidal, V.; Cano de Andrade, M. C.; Pfister, X.;Guerreiro, P.; Lenoir, J. Y. Tetrahedron Lett. 1995, 36, 4801;Guerreiro, P.; Cano de Andrade, M. C.; Henry, J. C.; Tranchier, J. P.;Phansavath, P.; Ratvelomanana-Vidal, V.; Genet, J. P.; Homri, T.;Touati, A. R.; Ben Hassine, B. C.R. Acad. Sci. Paris1999, 2, 175; whichare incorporated herein by reference; also reactions as described in“Catalytic Asymmetric Synthesis” by Ojima, published by Wiley-VGH (ISBN0-471-40027-0) and “Principle and Applications of Asymmetric Synthesisby Lin, Li and Chan published by Wiley inter-science (ISBN0-471-29805-0)) or a biological catalyst such as a whole cell, anenzyme, a cell preparation or a cell free extract.

Preferred catalysts are those asymmetric transfer hydrogenationcatalysts which are described in WO97/20789, WO98/42643, and WO02/44111which are herein incorporated by reference.

Particularly preferred transfer hydrogenation catalysts are those Ru, Rhor Ir catalysts of the type described in WO97/20789, WO98/42643, andWO02/44111 which comprise an optionally substituted diamine ligand, forexample optionally substituted ethylene diamine ligands, and a ligandwhich is selected from the group comprising optionally substitutedneutral aromatic ligands, for example p-cymene, and optionallysubstituted cyclopentadiene ligands. Examples include:

Especially preferred are Ru, Rh or Ir catalysts of the type described inWO97/20789, WO98/142643, and WO02/144111 which comprise an optionallysubstituted diamine ligand wherein at least one nitrogen atom of theoptionally substituted diamine ligand is substituted with a groupcontaining a chiral centre, particularly a sulphonyl group containing achiral centre.

Most preferred transfer hydrogenation catalysts for use in the processof the present invention have the general formula:

wherein:

-   -   R⁶ represents a neutral optionally substituted hydrocarbyl, a        neutral optionally substituted perhalogenated hydrocarbyl, or an        optionally substituted cyclopentadienyl ligand;    -   A represents an optionally substituted nitrogen;    -   B represents an optionally substituted nitrogen, oxygen, sulphur        or phosphorous;    -   E represents a linking group;    -   M represents a metal capable of catalysing transfer        hydrogenation; and    -   Y represents an anionic group, a basic ligand or a vacant site;    -   provided that at least one of A or B comprises a substituted        nitrogen and the substituent has at least one chiral centre; and    -   provided that when Y is not a vacant site that at least one of A        or B carries a hydrogen atom.

Preferably, A represents —NR⁷—, —NR⁸—, —NHR⁷, —NR⁷R⁸ or —NR⁸R⁹ where R⁷is H, C(O)R⁹, SO₂R⁹, C(O)NR⁹R¹³, C(S)NR⁹R¹³, C(═NR¹³)SR¹⁴ orC(═NR¹³)OR¹⁴, R⁸ and R⁹ each independently represents an optionallysubstituted hydrocarbyl, perhalogenated hydrocarbyl or an optionallysubstituted heterocyclyl group, and R¹³ and R¹⁴ are each independentlyhydrogen or a group as defined for R⁹; and B represents —O—, —OH, OR¹⁰,—S—, —SH, SR¹⁰, —NR¹⁰—, —NR¹¹—, —NHR¹¹, —NR¹⁰R¹¹, —NR¹⁰R¹², —PR¹⁰— or—PR¹⁰R¹² where R¹¹ is H, C(O)R¹², SO₂R¹², C(O)NR¹²R¹⁵, C(S)NR¹²R¹⁵,C(═NR¹⁵)SR¹⁶ or C(═NR¹⁵)OR¹⁶, R¹⁰ and R¹² each independently representsan optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or anoptionally substituted heterocyclyl group, and R¹⁵ and R¹⁶ are eachindependently hydrogen or a group as defined for R¹²; provided that atleast one of A or B comprises a substituted nitrogen and thesubstituent, represented by R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹², has at leastone chiral center.

More preferably, A represents —NR⁷—, —NR⁸—, —NHR⁷, —NR⁷R⁸ or —NR⁸R⁹where R⁷ is H, C(O)R⁹, SO₂R⁹, C(O)NR⁹R¹³, C(S)NR⁹R¹³, C(═NR¹³)SR¹⁴ orC(═NR¹³)OR¹⁴, R⁸ and R⁹ each independently represents an optionallysubstituted hydrocarbyl, perhalogenated hydrocarbyl or an optionallysubstituted heterocyclyl group, and R¹³ and R¹⁴ are each independentlyhydrogen or a group as defined for R⁹; and B represents —NR¹⁰—, —NR¹¹—,—NHR¹¹, —NR¹⁰R¹¹, or —NR¹⁰R¹² where R¹¹ is H, C(O)R¹², SO₂R¹²,C(O)NR¹²R¹⁵, C(S)NR¹²R¹⁵, C(═NR¹⁵)SR¹⁶ or C(═NR¹⁵)OR¹⁶, R¹⁰ and R¹² eachindependently represents an optionally substituted hydrocarbyl,perhalogenated hydrocarbyl or an optionally substituted heterocyclylgroup, and R¹⁵ and R¹⁶ are each independently hydrogen or a group asdefined for R¹²; provided that at least one of A or B comprises asubstituted nitrogen and the substituent, represented by R⁷, R⁸, R⁹,R¹⁰, R¹¹ or R¹², has at least one chiral center.

Preferably, when either of A or B is present as a group represented by—NR⁷—, —NHR⁷, NR⁷R⁸, —NR¹¹—, —NHR¹¹ or NR¹⁰R¹¹ wherein R⁸ and R¹⁰ are ashereinbefore defined, and where R⁷ or R¹¹ is a group represented byC(O)NR⁹R¹³, C(S)NR⁹R¹³, C(═NR¹³)SR¹⁴, C(═NR¹³)OR¹⁴, C(O)NR¹²R¹⁵,C(S)NR¹²R¹⁵, C(═NR¹⁵)SR¹⁶ or C(═NR¹⁵)OR¹⁶, that at least one of R⁹, R¹²,R¹⁴, R¹⁵ or R¹⁶ is an optionally substituted hydrocarbyl, perhalogenatedhydrocarbyl or an optionally substituted heterocyclyl group having atleast one chiral center.

More preferably, when either A or B is an amide group represented by—NR⁷—, —NHR⁷, NR⁷R⁸, —NR¹¹—, —NHR¹¹ or NR¹⁰R¹¹ wherein R⁸ and R¹⁰ are ashereinbefore defined, and where R⁷ or R¹¹ is an acyl group representedby —C(O)R⁹ or —C(O)R¹², that R⁹ and R¹² is an optionally substitutedhydrocarbyl, perhalogenated hydrocarbyl or an optionally substitutedheterocyclyl group having at least one chiral center. Examples of acylgroups which may be represented by R⁷ or R¹¹ include(R)-2-methyl-2-(4-methylphenyl)ethanoyl;(R)-2-methyl-2-(4-isobutylphenyl)ethanoyl;(R)-2-methyl-2-(6-methoxy-2-naphthyl)ethanoyl;(S)-2-hydroxy-2-(2-chlorophenyl)ethanoyl; and(R)-2-methyl-2-(3-pyridyl)ethanoyl.

Most preferably, when either A or B is present as a sulphonamide grouprepresented by —NR⁷—, —NHR⁷, NR⁷R⁸, —NR¹¹—, —NHR¹¹ or NR¹⁰R¹¹ wherein R⁸and R¹⁰ are as hereinbefore defined, and where R⁷ or R¹¹ is a sulphonylgroup represented by —S(O)₂R⁹ or —S(O)₂R¹², that R⁹ and R¹² is anoptionally substituted hydrocarbyl, perhalogenated hydrocarbyl or anoptionally substituted heterocyclyl group having at least one chiralcenter. Preferred sulphonyl groups include (1R)1-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl, (1S)1-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl, (1R,2S)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1R,2R)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1S,2R)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1S,2S)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl, (2S)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-ethansulfonyl, (2R)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-ethansulfonyl, (2S)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-methansulfonyl, (2R)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-methansulfonyl, (1R,2R,5R)5-isopropyl-2-methylcyclohexansulfonyl, and (1S,2S,5R)5-isopropyl-2-methylcyclohexansulfonyl, (1S,2S,5R)2-isopropyl-5-methylcyclohexansulfonyl.

It will be recognised that the precise nature of A and B will bedetermined by whether A and/or B are formally bonded to the metal or arecoordinated to the metal via a lone pair of electrons.

Hydrocarbyl groups which may be represented by one or more of R⁸⁻¹⁰ andR¹²⁻¹⁶, include alkyl, alkenyl, alkynyl and aryl groups, and anycombination thereof, such as aralkyl and alkaryl, for example benzyl,alpha-methylbenzyl and trityl groups.

Alkyl groups which may be represented by one or more of R⁸⁻¹⁰ and R¹²⁻¹⁶include linear and branched alkyl groups comprising up to 20 carbonatoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5carbon atoms. When the alkyl groups are branched, the groups oftencomprise up to 10 branched chain carbon atoms, preferably up to 4branched chain atoms. In certain embodiments, the alkyl group may becyclic, commonly comprising from 3 to 10 carbon atoms in the largestring and optionally featuring one or more bridging rings. Examples ofalkyl groups which may be represented by R⁸⁻¹⁰ and R¹²⁻¹⁶ includemethyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexylgroups.

Alkenyl groups which may be represented by one or more of R⁸⁻¹⁰ andR¹²⁻¹⁶ include C₂₋₂₀, and preferably C₂₋₆ alkenyl groups. One or morecarbon—carbon double bonds may be present. The alkenyl group may carryone or more substituents, particularly phenyl substituents. Examples ofalkenyl groups include vinyl, styryl, cyclohexenyl, cyclopentenyl andindenyl groups.

Alkynyl groups which may be represented by one or more of R⁸⁻¹⁰ andR¹²⁻¹⁶ include C₂₋₂₀, and preferably C₂₋₁₀ alkynyl groups. One or morecarbon—carbon triple bonds may be present. The alkynyl group may carryone or more substituents, particularly phenyl substituents. Examples ofalkynyl groups include ethynyl, propyl and phenylethynyl groups.

Aryl groups which may be represented by one or more of R⁸⁻¹⁰ and R¹²⁻¹⁶may contain 1 ring or 2 or more fused rings which may includecycloalkyl, aryl or heterocyclic rings. Examples of aryl groups whichmay be represented by R⁸⁻¹⁰ and R¹²⁻¹⁶ include phenyl, tolyl,fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl,naphthyl and ferrocenyl groups. Perhalogenated hydrocarbyl groups whichmay be represented by one or more of R⁸⁻¹⁰ and R¹²⁻¹⁶ independentlyinclude perhalogenated alkyl and aryl groups, and any combinationthereof, such as aralkyl and alkaryl groups. Examples of perhalogenatedalkyl groups which may be represented by R⁸⁻¹⁰ and R¹²⁻¹⁶ include —CF₃,—C₂F₅ and C₈H₃F₁₅.

Heterocyclic groups which may be represented by one or more of R⁸⁻¹⁰ andR¹²⁻¹⁶ independently include aromatic, saturated and partiallyunsaturated ring systems and may comprise 1 ring or 2 or more fusedrings which may include cycloalkyl, aryl or heterocyclic rings. Theheterocyclic group will contain at least one heterocyclic ring, thelargest of which will commonly comprise from 3 to 7 ring atoms in whichat least one atom is carbon and at least one atom is any of N, O, S orP. Examples of heterocyclic groups which may be represented by R⁸⁻¹⁰ andR¹²⁻¹⁶ include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl,indolyl, quinolyl, isoquinolyl, imidazoyl, oxazolyl, piperidinyl,morpholinyl and triazoyl groups.

When any of R⁸⁻¹⁰ and R¹²⁻¹⁶ is a substituted hydrocarbyl orheterocyclic group, the substituent(s) should be such so as not toadversely affect the rate or stereoselectivety of the reaction. Optionalsubstituents include halogen, cyano, nitro, hydroxy, amino, imino,thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl,hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters,carboxy, carbonates, amides, sulphonyl and sulphonamido groups whereinthe hydrocarbyl groups are as defined for R⁸ above. One or moresubstituents may be present. R⁸⁻¹⁰ and R¹²⁻¹⁶ may each contain one ormore chiral centres.

The neutral optionally substituted hydrocarbyl or perhalogenatedhydrocarbyl ligand which may be represented by R⁶ includes optionallysubstituted aryl and alkenyl ligands.

Optionally substituted aryl ligands which may be represented by R⁶ maycontain 1 ring or 2 or more fused rings which include cycloalkyl, arylor heterocyclic rings. Preferably, the ligand comprises a 6 memberedaromatic ring. The ring or rings of the aryl ligand are oftensubstituted with hydrocarbyl groups. The substitution pattern and thenumber of substituents will vary and may be influenced by the number ofrings present, but often from 1 to 6 hydrocarbyl substituent groups arepresent, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl,ethyl, iso-propyl, menthyl, neomenthyl and phenyl. Particularly when thearyl ligand is a single ring, the ligand is preferably benzene or asubstituted benzene. When the ligand is a perhalogenated hydrocarbyl,preferably it is a polyhalogenated benzene such as hexachlorobenzene orhexafluorobenzne. When the hydrocarbyl substitutents containenantiomeric and/or diastereomeric centres, it is preferred that theenantiomerically and/or diastereomerically purified forms of these areused. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especiallypreferred ligands.

Optionally substituted alkenyl ligands which may be represented by R⁶include C₂₋₃₀, and preferably C₆₋₁₂, alkenes or cycloalkenes withpreferably two or more carbon—carbon double bonds, preferably only twocarbon-carbon double bonds. The carbon—carbon double bonds mayoptionally be conjugated to other unsaturated systems which may bepresent, but are preferably conjugated to each other. The alkenes orcycloalkenes may be substituted preferably with hydrocarbylsubstituents. When the alkene has only one double bond, the optionallysubstituted alkenyl ligand may comprise two separate alkenes. Preferredhydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl.Examples of optionally substituted alkenyl ligands includecyclo-octa-1,5-diene and 2,5-norbornadiene. Cyclo-octa-1,5-diene isespecially preferred.

Optionally substituted cyclopentadienyl groups which may be representedby R⁶ includes cyclopentadienyl groups capable of eta-5 bonding. Thecyclopentadienyl group is often substituted with from 1 to 5 hydrocarbylgroups, preferably with 3 to 5 hydrocarbyl groups and more preferablywith 5 hydrocarbyl groups. Preferred hydrocarbyl substituents includemethyl, ethyl and phenyl. When the hydrocarbyl substitutents containenantiomeric and/or diastereomeric centres, it is preferred that theenantiomerically and/or diastereomerically purified forms of these areused. Examples of optionally substituted cyclopentadienyl groups includecyclopentadienyl, pentamethyl-cyclopentadienyl,pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl,ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl,neomenthyl-tetraphenylcyclopentadienyl, menthylcyclopentadienyl,neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyland neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl isespecially preferred.

Metals which may be represented by M include metals which are capable ofcatalysing transfer hydrogenation. Preferred metals include transitionmetals, more preferably the metals in Group VIII of the Periodic Table,especially ruthenium, rhodium or iridium. When the metal is ruthenium itis preferably present in valence state II. When the metal is rhodium oriridium it is preferably present in valence state I when R⁶ is a neutraloptionally substituted hydrocarbyl or a neutral optionally substitutedperhalogenated hydrocarbyl ligand, and preferably present in valencestate III when R⁶ is an optionally substituted cyclopentadienyl ligand

Anionic groups which may be represented by Y include hydride, hydroxy,hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when ahalogen is represented by Y, the halogen is chloride. When ahydrocarbyloxy or hydrocarbylamino group is represented by Y, the groupmay be derived from the deprotonation of the hydrogen donor utilised inthe reaction.

Basic ligands which may be represented by Y include water, C₁₋₄alcohols, C₁₋₈ primary or secondary amines, or the hydrogen donor whichis present in the reaction system. A preferred basic ligand representedby Y is water.

The groups A and B are connected by a linking group E. The linking groupE achieves a suitable conformation of A and B so as to allow both A andB to bond or coordinate to the metal, M. A and B are commonly linkedthrough 2, 3 or 4 atoms. The atoms in E linking A and B may carry one ormore substituents. The atoms in E, especially the atoms alpha to A or B,may be linked to A and B, in such a way as to form a heterocyclic ring,preferably a saturated ring, and particularly a 5, 6 or 7-membered ring.Such a ring may be fused to one or more other rings. Often the atomslinking A and B will be carbon atoms. Preferably, one or more of thecarbon atoms linking A and B will carry substituents in addition to A orB. Substituent groups include those which may substitute R⁸, as definedabove. Advantageously, any such substituent groups are selected to begroups which do not coordinate with the metal, M. Preferred substituentsinclude halogen, cyano, nitro, sulphonyl, hydrocarbyl, perhalogenatedhydrocarbyl and heterocyclyl groups as defined above. Most preferredsubstituents are C₁₋₆ alkyl groups, and phenyl groups.

Most preferably, A and B are linked by two carbon atoms, and especiallyan optionally substituted ethyl moiety. When A and B are linked by twocarbon atoms, preferably one or both of the carbon atoms are substitutedor the two carbon atoms linking A and B may comprise part of an aromaticor aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Sucha ring may be fused to one or more other such rings. Particularlypreferred are embodiments in which E represents a 2 carbon atomseparation and one or both of the carbon atoms carries an optionallysubstituted aryl group as defined above or E represents a 2 carbon atomseparation which comprises a cyclopentane or cyclohexane ring,optionally fused to a phenyl ring.

E preferably comprises part of a compound having at least onestereospecific centre. Where any or all of the 2, 3 or 4 atoms linking Aand B are substituted so as to define at least one stereospecific centreon one or more of these atoms, it is preferred that at least one of thestereospecific centres be located at the atom adjacent to either group Aor B. When at least one such stereospecific centre is present, it isadvantageously present in an enantiomerically purified state.

When B represents —O— or —OH, and the adjacent atom in E is carbon, itis preferred that B does not form part of a carboxylic group.

Compounds which may be represented by A-E-B, or from which A-E-B may bederived by deprotonation, are often substituted aminoalcohols, includingsubstituted 4-aminoalkan-1-ols, substituted 1-aminoalkan-4-ols,substituted 3-aminoalkan-1-ols, substituted 1-aminoalkan-3-ols, andespecially substituted 2-aminoalkan-1-ols, substituted1-aminoalkan-2-ols, substituted 3-aminoalkan-2-ols and substituted2-aminoalkan-3-ols, and particularly substituted 2-aminoethanols orsubstituted 3-aminopropanols, or are substituted diamines, includingsubstituted 1,4-diaminoalkanes, substituted 1,3-diaminoalkanes,especially substituted 1,2- or 2,3-diaminoalkanes and particularlysubstituted ethylenediamines. Further substituted aminoalcohols that maybe represented by A-E-B are substituted 2-aminocyclopentanols andsubstituted 2-aminocyclohexanols, preferably fused to a phenyl ring.Further diamines that may be represented by A-E-B are substituted1,2-diaminocyclopentanes and substituted 1,2-diaminocyclohexanes,preferably fused to a phenyl ring. When a diamine is represented byA-E-B, preferably at least one amino group is N-sulphonated with achiral sulphonyl group, preferably camphor sulphonyl. The aminoalcoholsor diamines are substituted on nitrogen with a substitutent containing achiral centre, advantageously the aminoalcohols or diamines are alsosubstituted on the linking group, E, by at least one alkyl group, suchas a C₁₋₄-alkyl, and particularly a methyl, group or at least one arylgroup, particularly a phenyl group.

Specific examples of compounds which can be represented by A-E-B and theprotonated equivalents from which they may be derived are:

Preferably, the enantiomerically and/or diastereomerically purifiedforms of these are used. Examples include (1R)1-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl, (1S)1-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl, (1R,2S)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1R,2R)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1S,2R)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1S,2S)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl(2S)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-ethansulfonyl, (2R)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-ethansulfonyl, (2S)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-methansulfonyl, (2R)1-(6,6-dimethylbicydo[3.1.1]hept-2-ene)-2-methansulfonyl, (1R,2R,5R)5-isopropyl-2-methylcyclohexansulfonyl, (1S,2S,5R)5-isopropyl-2-methylcyclohexansulfonyl, and (1S,2S,5R)2-isopropyl-5-methylcyclohexansulfonyl.

Most preferably, the nature of A-E-B, R⁶ and Y are chosen such that thecatalyst is chiral. When such is the case, an enantiomerically and/ordiastereomerically purified form is preferably employed.

Examples of these preferred catalysts which may be employed in theprocess of the present invention include:

One example of these especially preferred catalysts can be prepared byreacting rhodium pentamethylcyclopentadiene dichloride dimer with(S)-N-camphorsulphonyl-(S,S)-diphenylethylenediamine under theconditions described in Example 6 of WO98/42643 to give a catalyst ofFormula:

Other examples of these especially preferred catalysts includechlororhodium-eta-5-pentamethylcyclopentadienylN-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5pentamethylcyclopentadienylN-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1R,2R)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1R,2S)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S,2R)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-[(1S,2S)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1R,2R)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1R,2S)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide,chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S,2R)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide,and chlororhodium-eta-5-pentamethylcyclopentadienylN-[(1R,2R)-2-amino-1,2-diphenylethyl]-1-[(1S,2S)-7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl]methanesulfonamide.

The reduction reaction may optionally be carried out under biphasicconditions and is preferably carried out in the absence of oxygen, forexample under a nitrogen atmosphere. The preferred temperature range forthis reaction is −30 to 90° C., especially 0 to 50° C.

When X is S, preferred compounds of Formula (2), including compounds ofFormula (8):

where R⁵ is optionally substituted C₁₋₈alkyl.

may be prepared by reacting 2-acetyl thiophene with a dialkyl carbonate,more preferably diethyl carbonate, in the presence of a base preferablyan alkali salt of the alkyl salt corresponding to the dialkylcarbonate(eg sodium ethoxide if the dialkyl carbonate is diethyl carbonate), anon-nucleophilic base such as NaOtBu, KOtBu, LiOtBu, lithiumdiisopropylamide, Na, K or Li hexamethyldisylazide, Na in liquidammonia, sodamide or an amine base with an activating Lewis acid (egtriethylamine with a Mg salt). Especially preferred bases are hydridesalts, particularly sodium hydride and non-nucleophilic bases,particularly NaOtBu.

R⁵ is preferably optionally substituted C₁₋₄alkyl and especially ethyl.

The compound of Formula (8) is then preferably reduced by astereospecific reduction, as described above, to give a compound ofFormula (9):

where R⁵ is as described above.

The amidation of the compound of Formula (2) in step (a) may be carriedout by any means known in the art.

Preferably Step (a) of the process is performed in the presence of anyorganic solvent or mixture of organic solvents which is unreactivetowards the reagents employed. Polar aprotic solvents are especiallyfavoured. Examples of suitable solvents include toluene,tetrahydrofuran, acetonitrile, DMF and ethers.

Step (a) of the invention is preferably carried out in the temperaturerange of from −20° C. to 150° C. More preferably in the temperaturerange of from −10° C. to 100° C.

Step (a) of the process is advantageously allowed to proceed to at least90% and more advantageously at least 95% conversion to a compound ofFormula (3).

The reaction time of step (a) of the process of the second aspect of theinvention will depend on a number of factors, for example the reagentconcentrations, the relative amounts of reagents, the presence of acatalyst, the nature of the solvent and particularly the reactiontemperature. Typical reaction times, in addition to the reagent additiontimes, range from 1 minute to 200 h hours, with reaction times of 5minutes to 6 hours being common.

When, in a preferred embodiment of the invention, one of R¹ and R² is Hand the other is methyl, then step (a) preferably comprises reacting acompound of Formula (2) with methylamine.

It is particularly preferred that the compound of Formula (2) andmethylamine are both in solution in either a single or multiphasesystem.

A preferred solvent system for step (a) comprises water and a waterimmiscible solvent, especially toluene.

The reduction of the compound of Formula (3) in step (b) may be carriedout using any suitable method known in the art. These methods includereduction by: lithium aluminium hydride, di-iso-butylaluminium hydride,lithium borohydride, lithium borohydride with methanol, catecholboraneor borane or sodium borohydride preferably with an activating agent suchas ethanol, CH₃SO₂H, H₂SO₄, pyridine, methanol, TiCl₄ or CoCl₂.

Preferably reduction of the compound of Formula (3) in step (b) is bylithium aluminium hydride.

Step (b) of the process can be performed without any solvent but ispreferably performed in the presence of any organic solvent or mixtureof organic solvents which is unreactive towards the reagents employed.Examples of suitable solvents include toluene, methanol, hexane,tetrahydrofuran, ethylacetate, octanol, acetonitrile anddimethylformamide. Tetrahydrofuran is especially favoured.

Step (b) of the process is preferably performed in the absence ofoxygen. Oxygen may be excluded by, for example, passing an inert gas,especially nitrogen, through the reaction mixture.

Step (b) of the process may be carried out under reduced pressure.

Step (b) of the second aspect of the invention is preferably carried outin the temperature range of from −20° C. to 150° C. and more preferablyin the temperature range of from 10° C. to 70° C.

Step (b) of the process of the second aspect of the invention isadvantageously allowed to proceed to at least 90% conversion and morepreferably to at least 95% conversion, to a compound of Formula (1).

The reaction time of step (b) of the process of the second aspect of theinvention will depend on a number of factors, for example the reagentconcentrations, the relative amounts of reagents and particularly thereaction temperature. Typical reaction times, in addition to the reagentaddition times, range from 1 minute to 200 hours, with reaction times of2 hours to 48 hours being common.

A preferred embodiment of the present invention provides a process forthe preparation of a compound of Formula (10):

which comprises the steps:

-   (a) reacting a compound of Formula (9):

where R⁵ is optionally substituted C₁₋₈alkyl, with methylamine to give acompound of Formula (11):

and

-   (b) reducing the compound of Formula (11) to give the compound of    Formula (10).

The preferred reductant in step (b) is lithium aluminium hydride.

A more preferred embodiment of the present invention provides a processfor the preparation of a compound of Formula (10):

which comprises the steps:

-   (i) acetylating 2-acetyl thiophene to give the compound of Formula    (8):

where R⁵ is optionally substituted C₁₋₈alkyl;

-   (ii) reducing the compound of Formula (8) to give the compound of    Formula (9):

where R⁵ is optionally substituted C₁₋₈alkyl;

-   (iii) reacting a compound of Formula (9) with methylamine to give a    compound of Formula (11):

and

-   (iv) reducing the compound of Formula (11) to give the compound of    Formula (10).

Conditions for steps (i) to (iv) are as described and as preferredabove.

According to a fourth aspect of the invention there is provided acompound of Formula (3) as defined above.

In preferred compounds of Formula (3) R and X are as preferred in thefirst aspect of the invention.

A preferred compound of Formula (3) is of Formula (12):

A more preferred compound of Formula (3) is of Formula (11).

Many of the compounds of Formulae (1) to (12) may exist in the form of asalt. These salts are included within the scope of the presentinventions.

The compounds of Formulae (1) to (12) may be converted to the salt formusing known techniques.

The compounds of Formulae (1) to (12) may exist in tautomeric formsother than those shown in this specification. These tautomers are alsoincluded within the scope of the present inventions.

The invention will now be illustrated, without limitation, by thefollowing examples.

EXAMPLE 1 Stage 1 Preparation of ethyl-3-oxo 3-(2-thiophenyl)propanoate

Sodium hydride (60% dispersion in mineral oil, 100 g, 2.5 mol) waswashed with anhydrous hexane (2×250 ml) under a nitrogen atmosphere atroom temperature. Anhydrous tetrahydrofuran (THF) (340 ml) was thenadded with stirring followed by 2-acetyl thiophene (136 ml, 1.25 mol) inanhydrous THF (340 ml) over period of 20 minutes. The reaction mixturewas then warmed to 35° C. After 30 minutes diethyl carbonate (305.5 ml,2.5 mol) in anhydrous THF (660 ml) was added over a period of 1 hour.After an additional hour the reaction mixture was cooled to −10° C.,quenched with water (475 ml) and glacial acetic acid (145 ml) was added.The mixture was stirred for 20 minutes and then warmed to roomtemperature. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (3×200 ml). The combined organic extractswere washed with brine (2×200 ml), dried with Na₂SO₄ and concentratedunder reduced pressure to give the title compound as a crude dark orangeoil in 98% yield (242.8 g).

Stage 2 Preparation of ethyl-3-(S)-hydroxy 3-(2-thiophenyl)propanoate

Rhodium pentamethylcyclopentadiene dichloride dimer (1.8705 g, 0.0030mol) and (S)-N-camphorsulphonyl-(S,S)-diphenylethylenediamine (2.582 g,0.0061 mol) were stirred in THF (378.5 ml) at 0° C. under nitrogen toform a catalytic solution.

Ethyl-3-oxo 3-(2-thiophenyl)propanoate (300 g, 1.513 mol, from stage 1)was stirred in THF (378.5 ml) at 10° C. and sparged with nitrogen at arate of 1.2 Lmin⁻¹. A portion of the catalytic solution (78.5 ml) wasadded, and a mixture of formic acid and triethylamine in a molar ratioof 5:2 (327.1 g) was charged at a rate of 52.1 mlhr⁻¹. Further portionsof the catalytic solution (75 ml) were added every 1.5 hr. After thereaction had been shown to have gone to completion by GC, after about 24hours, saturated aqueous sodium hydrogen carbonate solution (1 L) wasadded at room temperature to quench the reaction. The aqueous layer wasextracted with toluene (400 ml). The combined organic layers were washedwith brine (400 ml, 10% w/w solution) and dried over anhydrous sodiumsulphate. The organic solution was concentrated under reduced pressureto give a dark brown oil in 97.5% yield (295.4 g).

Stage 3 Preparation of 3-(S)-hydroxy-N-methyl3-(2-thiophenyl)propanamide

Ethyl-3-(S)-hydroxy 3-(2-thiophenyl)propanoate (270 g, from stage 2) wasdissolved in toluene (675 ml). To this, an aqueous methylamine solution(675 ml, 40% w/w) was added with stirring over a period of 15 minutes atroom temperature. Once the reaction had gone to completion after 1 hour,agitation was ceased and the organic layer was separated from theaqueous layer. Salt (100 g) was added to the aqueous layer which wasthen extracted with isopropyl acetate (2×500 ml). The organic extractsand the original organic layer were combined. Silica (250 g) was addedand the resulting suspension was stirred for 20 minutes. The mixture wasfiltered and silica (250 g) was again added and the mixture was stirredfor 20 minutes before being filtered. The resulting solution wasconcentrated under reduced pressure to give orange crystals (90.5 g,36%) as the product.

Stage 4 Preparation of (S)-3-(N-methyl)amino 1-(2-thiophenyl)propan-1-ol

3-(S)-Hydroxy-N-methyl 3-(2-thiophenyl)propanamide (80 g) was dissolvedin anhydrous THF (320 ml) under nitrogen with stirring. A solution oflithium aluminium hydride (648 ml, 1 M) in THF was added at rate thatkept the temperature constant at 50° C. When all the lithium aluminiumhydride solution had been added the reaction mixture was held at 50° C.for 50 minutes. The mixture was then cooled to −10° C. and isopropanol(100 ml) was slowly added. A saturated sodium sulphate solution (310 ml)was then added and the mixture was filtered. The filter residues werewashed with ethyl acetate (2×100 ml) and the aqueous layer wasseparated. The organic layer was washed with saturated brine (2×100 ml)and then dried over sodium sulphate. The organic solution was thenconcentrated under reduced pressure to give a dark orange oil (65 g,88%). Solvating the oil in toluene and stirring at 0° C. overnight gavecrystals as the final product that were filtered and dried on thefilter.

EXAMPLE 2 Preparation of ethyl-3-(S)-hydroxy 3-(2-thiophenyl)propanoateby biological reduction of ethyl-3-oxo 3-(2-thiophenyl)propanoate

Yeast cultures were grown on YM (yeast and mold) agar at 28° C. for 72h. Liquid cultures were prepared by inoculating a single colony from aplate into 50 ml of sterile growth medium consisting of (per litre);glucose (10 g), yeast extract (2 g), trace metal solution (1 ml), K₂HPO₄(1.9 g), NaH₂PO₄ 2H₂O (2.02 g), (NH₄)₂SO₄ (1.8 g), MgSO₄ 7H₂O (0.2 g)and FeCl₃ (0.97 mg) in a 250 ml baffled flask. Following 24 h growth at28° C. on an orbital shaker, the cells were harvested by centrifuging at4000 rpm for 10 minutes and the cell pellet was resuspended in 5 ml of0.1M phosphate buffer, pH 7.5. The cell suspension was centrifuged asabove, the supernatant discarded and the cell pellet resuspended in 5 mlof the above buffer. Bioreductions were initiated by the addition of 5ml of cell suspension to 5 ml of the above buffer containing 4 g/lglucose and 20 ul of ethyl-3-oxo 3-(2-thiophenyl)propanoate from Example1 stage 1. The cells were incubated for 24 h at 28° C. on an orbitalshaker. Formation of ethyl-3-hydroxy 3-(2-thiophenyl) propanoate wasmonitored by removing 1 ml of cell suspension, centrifuging at 14K rpmfor 1 minute to pellet the cells and analysing the supernatant byreverse phase HPLC. Analysis was performed on a Hichrom RPB column (25cm×4.6 mm i.d.) eluted at 1 ml/min with 0.1% aqueous TFA andacetonitrile (70:30) at a column temperature of 28° C. The reactant andproduct were detected by their absorbance at 254 nm. The retention timeof ethyl-3-oxo 3-(2-thiophenyl)propanoate was 12.7 minutes and theretention time of ethyl-3-hydroxy 3-(2-thiophenyl)propanoate was 9.3minutes. Bioreduction reactions showing the formation of ethyl-3-hydroxy3-(2-thiophenyl)propanoate were worked up by centrifuging at 4K rpm for10 minutes and extracting the supernatant twice with an equal volume ofmethyl-tert-butylether. The combined extracts were dried over anhydroussodium sulphate and then the solvent was evaporated to dryness. Theresidue was taken up in isohexane and 2-propanol (70:30) and theenantiomeric composition of the ethyl-3-hydroxy3-(2-thiophenyl)propanoate was determined by chiral phase HPLC. Analysiswas performed on a Chiralcel OD column (25 cm×4.6 mm i.d. ex Daicel Ltd)eluted at 1 ml/min with isohexane and 2-propanol (90:10) at a columntemperature of 28° C. Ethyl-3-oxo 3-(2-thiophenyl)propanoate and theenantiomers of ethyl-3-hydroxy 3-(2-thiophenyl) propanoate were detectedby their absorbance at 235 nm. The retention time of ethyl-3-oxo3-(2-thiophenyl)propanoate was 16.5 minutes, the retention time ofethyl-3-(S)-hydroxy 3-(2-thiophenyl)propanoate was 10.3 minutes and theretention time of ethyl-3-(R)-hydroxy 3-(2-thiophenyl)propanoate was24.0 minutes. The results are summarised in the following table.

% Conversion to ethyl-3-(R)- hydroxy 3-(2- thiophenyl) % e. e. of (S)Microorganism propanoate enantiomer Saccharomyces carlsbergensis 4 79NCYC398 Hansenula wickerhamii 51 61 CBS4307 Saccharomyces cerevisiae 2680 CBS431 Pichia pastoris CBS704 17 82 Debaromyces marama NCYC282 12 92Hansenula philodendra 10 91 CBS6075 Candida intermedia IFO0761 18 76Pichia angusta NCYCR320 46 80 Candida boidinii CBS2420 66 98 Hansenulanonfermentans 65 84 CBS5674 Hansenula angusta BCC426 39 93 Torulopsissp. BCC900 25 78 Torulopsis molischiana 64 85 CBS837

1. A catalyst of formula:

wherein: R⁶ represents a neutral optionally substituted hydrocarbyl, aneutral optionally substituted perhalogenated hydrocarbyl, or anoptionally substituted cyclopentadienyl ligand; each of A and B ispresent as a sulphonamide group represented by —NR⁷—, —NHR⁷, NR⁷R⁸,—NR¹¹—, —NHR¹¹ or NR¹⁰R¹¹ wherein R⁸ and R¹⁰ are each independentlyoptionally substituted hydrocarbyl, perhalogenated hydrocarbyl or anoptionally substituted heterocyclyl group, and where R⁷ and R¹¹ is asulphonyl group represented by —S(O)₂R⁹ or —S(O)₂R¹², wherein R⁹ and R¹²is an optionally substituted hydrocarbyl group which is a cyclic alkylgroup comprising from 3 to 10 carbon atoms in the largest ring andoptionally including one or more bridging groups; E represents a linkinggroup; M represents a metal capable of catalysing transferhydrogenation; and Y represents an anionic group, a basic ligand or avacant site; provided that when Y is not a vacant site, at least one ofA or B carries a hydrogen atom.
 2. A catalyst according to claim 1wherein one of R⁷ or R¹¹ is (1R)1-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl, (1S)1-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl, (1R,2S)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1R,2R)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1S,2R)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl,(1S,2S)1-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]hept-1-yl)methanesulfonyl, (2S)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-ethansulfonyl, (2R)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-ethansulfonyl,(2S)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-methansulfonyl, (2R)1-(6,6-dimethylbicyclo[3.1.1]hept-2-ene)-2-methansulfonyl, (1R,2R,5R)5-isopropyl-2-methylcyclohexansulfonyl, or (1S,2S,5R)5-isopropyl-2-methylcyclohexansulfonyl, (1S,2S,5R)2-isopropyl-5-methylcyclohexansulfonyl.
 3. A catalyst according to claim1 wherein E is a linking group such that A and B are linked through 2, 3or 4 atoms which are optionally substituted.